Capitalizing on a rare opportunity to thoroughly analyze a tumor from a lung cancer patient who had developed resistance to targeted drug treatment, UC-San Francisco (UCSF) scientists identified a biological escape hatch that explains the resistance, and developed a strategy in mice for shutting it down. In experiments that combined the drug the patient had taken with a second compound that blocks off this newly discovered resistance pathway, the researchers were able to durably wipe out cancer cells in mice implanted with cells from the drug-resistant human tumor. "Even in cancers that are responding to targeted therapy by conventional criteria, resistance is already developing," said the senior author of the new study, Trever Bivona, M.D., Ph.D., Assistant Professor of Medicine and member of the UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC). "In this work we have begun to crack open the question of why residual disease persists after targeted therapy." Between 10 and 35 percent of non-small cell lung cancer (NSCLC) patients carry mutations in a gene that codes for a cell-surface protein called the epidermal growth factor receptor (EGFR). As its name suggests, under normal circumstances, when a growth factor protein locks onto the EGFR, the receptor sends signals that prompt cells to divide and proliferate. But the EGFR mutations seen in NSCLC cause the receptor to be stuck in an "on" position, leading to rampant cell proliferation. Over the past decade, medications such as erlotinib (trade name Tarceva), which precisely targets the EGFR and tamps down its activity, have advanced the treatment of EFGR-mutant NSCLC beyond chemotherapy, but significant challenges remain.
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